Hepatic encephalopathy: Suspect it early in patients with cirrhosis
ABSTRACTAs viral hepatitis and nonalcoholic fatty liver disease continue to increase in prevalence, we will see more cases of hepatic encephalopathy. Primary care physicians are often the first to suspect it, as they are familiar with the patient’s usual mental and physical status. This serious complication typically occurs in patients with severe comorbidities and requires multidisciplinary evaluation and care.
KEY POINTS
- Hepatic encephalopathy should be considered in any patient with cirrhosis who presents with neuropsychiatric manifestations in the absence of another brain disorder, such as stroke or brain tumor.
- “Minimal” hepatic encephalopathy may not be obvious on clinical examination but can be detected with neurophysiologic and neuropsychiatric testing.
- Every cirrhotic patient is at risk; potential precipitating factors should be addressed during regular clinic visits.
- Management requires prompt identification of precipitating factors and initiation of empiric medical therapy. Current treatments include drugs to prevent ammonia generation in the colon.
- Long-acting benzodiazepines should not be used to treat sleep disorders in patients with cirrhosis, as they may precipitate encephalopathy.
Diet therapy
The prevalence of malnutrition in cirrhosis may be as high as 100%. Vitamin and nutritional deficiencies should be evaluated by a nutrition specialist, and nutritional needs should be reassessed on a regular basis. Protein restriction is no longer recommended and may even be harmful.
Guidelines of the European Society of Parenteral and Enteric Nutrition in 2006 recommended that patients with liver disease should have an energy intake of 35 to 40 kcal/kg of body weight daily, with a total daily protein intake of 1.2 to 1.5 mg/kg of body weight.41 Frequent meals and bedtime snacks are encouraged to avoid periods of prolonged fasting and catabolism of muscle protein and to improve nitrogen balance. Branched-chain amino acids and vegetable protein supplements are suggested to help meet the daily requirements.42
Drug therapy to reduce neurotoxins
Drug treatment is directed at reducing the neurotoxins that accumulate in cirrhosis. A variety of agents have been used.
Lactulose (Kristalose) is approved by the US Food and Drug Administration (FDA) as a first-line treatment. It has been shown to improve quality of life and cognitive function in patients with cirrhosis and minimal hepatic encephalopathy, although it has failed to improve mortality rates.37
Lactulose, a cathartic disaccharide, is metabolized by colonic bacteria into short-chain fatty acids. The acidic microenvironment has three major effects:
- It aids the transformation of ammonia to ammonium (NH4+), which is then trapped in the stool, leaving less ammonia to be absorbed
- It has a cathartic effect
- It reduces the breakdown of nitrogenous compounds into ammonia.43
Lactulose has an excessively sweet taste. Its side effects include flatulence, abdominal discomfort, and diarrhea. The usual oral dose is 15 to 45 mL/day given in multiple doses to induce two to three soft bowel movements daily. At this dosage, the monthly cost varies between $60 and $120.
Lactilol, a nonabsorbable disaccharide, is as effective as lactulose but with fewer side effects. It is not available in the United States.
Rifaximin (Xifaxan), a derivative of rifamycin, is FDA-approved for the maintenance of remission of hepatic encephalopathy but is not recommended as a first-line agent. It inhibits bacterial RNA synthesis in the gut. Less than 0.4% of an oral dose is absorbed.44
In a randomized, double-blind, placebo-controlled trial in patients who had had at least two episodes of hepatic encephalopathy while on lactulose therapy, taking rifaximin 550 mg twice a day for 6 months provided a prolonged remission from recurrences of encephalopathy compared with placebo.45 Side effects included nausea, vomiting, abdominal pain, weight loss, and Clostridium difficile colitis, which was reported in two cases in the study.45
Unfortunately, the effects of this drug beyond 6 months of therapy have not been studied. In addition, the drug is expensive: 1 month of treatment with rifaximin can cost between $700 and $1,500. Combining lactulose and rifaximin adds to the costs and the side effects, and contributes to poor adherence to therapy.
Other antibiotics such as metronidazole (Flagyl), vancomycin, and neomycin have been used as alternatives to lactulose, based on the principle that they reduce ammonia-producing bacteria in the gut. However, their efficacy in hepatic encephalopathy remains to be determined.
In controlled trials, neomycin combined with sorbitol, magnesium sulfate, or lactulose was as effective as lactulose, but when used alone, neomycin was no better than placebo.46,47 Neomycin was approved many years ago as an adjunct in the management of hepatic coma, but it has since fallen out of favor in the management of hepatic encephalopathy because of poor trial results and because of neurotoxicity and ototoxicity.
Branched-chain amino acids (leucine, isoleucine, and valine)48 are reported to increase ammonia intake in muscle and to improve cognitive functions on the PSE scale in minimal hepatic encephalopathy,49,50 but they did not decrease the rate of recurrence of hepatic encephalopathy.51 While debate continues over their efficacy in the management of hepatic encephalopathy, branched-chain amino acids may be used to improve nutritional status and muscle mass of patients with cirrhosis. However, the dosing is not standardized, and long-term compliance may be problematic.
Other medical therapies include zinc,16 sodium benzoate,50 and l-ornithine-l-aspartate52,53 to stimulate residual urea cycle activities; probiotics (which pose a risk of sepsis from fungi and lactobacilli); and laxatives.
Liver dialysis
Adsorbing toxins from the blood via liver dialysis or using a non-cell-based liver support system such as MARS (Molecular Adsorbent Recirculating System, Gambro, Inc.) appears to improve the amino acid profile in hepatic encephalopathy, but its role has not been clarified, and its use is limited to clinical trials.54,55
Transjugular intrahepatic shunts and large portosystemic shunts may need to be closed in order to reverse encephalopathy refractory to drug therapy.26,27,56
Liver transplantation
The current scoring system for end-stage liver disease does not include hepatic encephalopathy as a criterion for prioritizing patients on the transplantation list because it was originally developed to assess short-term prognosis in patients undergoing transjugular intrahepatic shunting. As a consequence, patients with end-stage liver disease are at increased risk of repeated episodes of encephalopathy, hospital readmission, and death. Therefore, the American Association for the Study of Liver Diseases recommends referral to a transplantation center when the patient experiences a first episode of overt hepatic encephalopathy to initiate a workup for liver transplantation.34
Liver transplantation improves survival in patients with severe hepatic dysfunction, but the presence of neurologic deficits may result in significant morbidity and in death.57,58 After transplantation, resolution of cognitive dysfunction, brain edema, and white-matter changes have been reported,59 but neuronal cell death and persistent cognitive impairment after resolution of overt hepatic encephalopathy are also described.60–63
Whether neurologic impairment will resolve after liver transplantation depends on a number of factors: the severity of encephalopathy before transplantation; the nature of the neurologic deficits; advanced age; history of alcohol abuse and the presence of alcoholic brain damage; persistence of portosystemic shunts after transplant; emergency transplantation; complications during surgery; and side effects of immunosuppressive drugs.57,58,64
The optimal timing of liver transplantation is not clearly defined for patients who have had bouts of hepatic encephalopathy, and more study is needed to determine the reversibility of clinical symptoms and brain damage. It is in these situations that neuropsychiatric testing and advanced neuroimaging can help determine the efficacy of therapeutic interventions, and it should be considered part of the pretransplantation evaluation.
Managing sleep disturbances
Insomnia and other changes in sleep-wake patterns are common in patients with cirrhosis, especially advanced cirrhosis.65 It is not known whether these changes represent early stages of hepatic encephalopathy.66 Patients often complain of fatigue, the need for frequent naps, and lethargy during the day and restlessness and inability to sleep at night. This affects the patient’s behavior and daytime functioning, and it also burdens household members and caregivers.
Long-acting benzodiazepines should be avoided when treating sleep disorders in cirrhosis because they may precipitate the encephalopathy. In a randomized controlled trial, hydroxyzine (Vistaril) at a dose of 25 mg at bedtime improved sleep behavior in 40% of patients with cirrhosis and subclinical hepatic encephalopathy, but 1 of 17 patients developed acute encephalopathy, which reversed with cessation of the hydroxyzine.66 Clearly, caution and close monitoring are required when giving hydroxyzine for sleep disorders in cirrhotic patients.
